This research program exploits seven important laboratory and epidemiologic advances in oncology to develop clinical applications designed to reduce the incidence and mortality of lung cancer. Crucial to all the studies is the development of the Biologic Resource Depository Core that will store patient specimens with their integrated clinical and laboratory data. 1. A proven correlation exists between a 2D6 P450 cytochrome phenotype and increased risk of lung cancer. Our first project proposes a case-control study to exploit polymorphic genotypes of a series of P450 cytochromes to determine a genetic predisposition to lung cancer. 2. Clinically evident lung cancer exhibits many mutations in the dominant and particularly the recessive oncogenes. We will determine whether a preferred order of molecular changes can be exploited to detect lung cancer in its very early stages. 3. Carcinogenic derivatives of nicotine (NNK) cause lung tumors in rodents and certain dietary elements can significantly reduce this tumorigenesis. We will focus on preclinical development of two chemopreventive agents in rodents and assess the effects of these agents on NNK adduct formation in humans, thereby developing the basis for use of these agents in clinical trials in individuals with increased risk of lung cancer. 4. Oncopeptide mutations produce epitopes which potentially could be detected by the immune system. We propose to test for such cellular and humoral immunity as part of a plan to develop tumor specific oncopeptide vaccines for clinical trial. 5. Heparin-steroid conjugates inhibit angiogenesis in selected tumors. We will conduct preclinical studies to identify the best conjugates and translate these into a clinical trial. 6. The in vitro growth of lung cancer cells is dramatically inhibited by methadone in association with novel, high affinity binding sites. We will conduct a phase I-II clinical trial to test whether methadone can cause lung cancer regression in patients. 7. Cytokine genes expressed in animal tumor cells can stimulate a systemic tumor specific immune response. We will use a new method of introducing cytokine genes into tumor cells in vivo to elicit a specific cytotoxic response. In summary, we will carry out seven interrelated projects which promise eventually to decrease the high mortality of lung cancer.